The objectives of this research are to explore the toxic limitations to antihypertensive therapy by a variety of drugs that are also capable of oxidizing hemoglobin. Our previous discovery that nitroprusside can penetrate the intact red cell and react with hemoglobin to liberate lethal levels of cyanide defined the toxic limitation to acute nitroprusside therapy. We suspect the toxic limitations of chronic nitroprusside therapy may be either a decrease in the oxygen transport capability of blood, or the accumulation of toxic blood levels of thiocyanate, or both. Since thiocyanate is also a potential antihypertensive drug but possesses unpredictable and poorly defined toxicity, we will examine its toxicology on a variety of species. We will attempt to define the conditions under which it is capable of generating methemoglobin and to elucidate its metabolism. Our understanding of nitroprusside toxicology has suggested alternative transition metal nitroso derivatives, particularly those of ruthenium, that will be screened for their ability to directly relax vascular smooth muscle and evaluated for toxic effects. We will attempt to gather evidence for the involvement of heme groups in some types of vascular smooth muscle receptors. Studies of chemically-induced abnormalities of hemoglobin will continue. We are also exploring a unique hematologic condition of high altitude exposure in mice, rats and cats, namely a hemoglobinemia which occurs in the face of a greatly elevated hematocrit. This phenomenon could serve as a useful model for factors limiting on the rate of hemoglobin catabolism.